1. Field of the Invention
The present invention concerns antiviral compounds, their methods of preparation and their compositions, and use in the treatment of viral infections. More particularly, the invention provides heterocyclic substituted 2-methylbenzimidazole derivatives for the treatment of respiratory syncytial virus infection.
2. Background Art
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract infection in infants, children, elderly and immunocompromised persons. A severe viral infection may result in bronchiolitis or pneumonia which may require hospitalization or result in death. (JAMA, 1997, 277, 12). Currently only Ribavirin is approved for the treatment of this viral infection. Ribavirin is a nucleoside analogue which is administered intranasally as an aerosol. The agent is quite toxic, and its efficacy has remained controversial. RespiGam, approved for prophylaxis in high risk pediatric patients, is an intravenous immunoglobulin which effectively neutralizes the virus. Recently, Synagis, a monoclonal antibody administered through intramuscular injection has also been approved for use in high risk pediatric patients. However, both drugs are very expensive. Accordingly, inexpensive, safe and effective antiviral agents against respiratory syncytial virus will be beneficial for patients.
Many agents are known to inhibit respiratory syncytial virus (De Clercq, Int. J. Antiviral Agents, 1996, 7, 193). Y. Tao et al. (EP 0 058 146 A1, 1998) disclosed that Ceterizine, a known antihistamine, exhibited anti-RSV activity. Tidwell et al., J. Med. Chem. 1983, 26, 294 (U.S. Pat. No. 4,324,794, 1982), and Dubovi et al., Antimicrobial Agents and Chemotherapy, 1981, 19, 649, reported a series of amidino compounds with the formula shown below as inhibitors of RSV. 
Hsu et al., U.S. Pat. No. 5,256,668 (1993) also disclosed a series of 6-aminopyrimidones that possess anti-viral activity against RSV. 
Y. Gluzman, et al., (AU Patent, Au-A-14,704, 1997) and P. R. Wyde et al. (Antiviral Res. 1998, 38, 31) disclosed a series of triazine containing compounds that were useful for the treatment and/or prevention of RSV infection. 
In addition, T. Nitz, et al., (WO Patent, WO 00/38508, 1999) disclosed a series of triaryl containing compounds that were useful for the treatment and/or prevention of RSV and related pneumoviral infections. 
Moreover, Yu et al. (WO 020004900) also disclosed a series of substituted benzimidazoles that is useful for the treatment and prevention of RSV infection. 
A related series of compounds were first disclosed by F. Pagani and F. Sparatore in Boll Chim Farm. 1965, 104, 427 and by G. Paglietti, et al. in Il Farmaco, Ed. Sci. 1975, 30, 505, and found to possess analgesic and anti-arrhythmic activity. The structural formula for these compounds are depicted in Formula Ia and Ib. 
In Formula Ia and Ib, A is xe2x80x94(CH2)n-N(R)2, n=2 or 3, R=Me or Et, or A is 
B=H, Cl, CF3, CH3CO, NO2.
Another series of closely related compounds that Sparatore had disclosed were in Il Farmaco Ed. Sci. 1967, 23, 344 (U.S. Pat. No. 3,394,141, 1968). Some of the compounds were reported to have analgesic, anti-inflammatory or anti-pyretic activities. The structure of these compounds is depicted in Formula Ic. In Formula Ic, C=H, CF3, or NO2. D is xe2x80x94(CH2)n-NR2, n=2 or 3, R=Me or Et, or D=
E is H, Cl or OEt. 
Another series of compounds structurally related to this invention are pyrido[1,2-a]benzoazoles and pyrimidio[1,2a]benzimidazoles disclosed by S. Shigeta et al in Antiviral Chem. and Chemother. 1992, 3, 171. These compounds have demonstrated inhibition of orthomyxovirus and paramyxovirus replication in HeLa cells. The structures of these compounds are shown in Formulas Id and Ie, in which F=NH, S, or O; Q=xe2x80x94NHCOPh, xe2x80x94COOH, COOEt, or CN; T=COMe, CN, or COOEt; G=O or NH. 
A bis-benzimidazole with an ethylenediol linker shown below has also been reported as a potent inhibitor of rhinoviruses (Roderick, et al. J. Med. Chem. 1972, 15, 655).
A series of 2-aminobenzimidazoles have been reported by E. Janssens, et al. as inhibitors of RSV in a series of recent publications and representative examples formula 1f-1h are shown below from PCT WO 01/00611 A1; PCT WO 01/00612 and PCT WO 01/00615, respectively all published on Jan. 4, 2001. 
A series of triazole containing compounds have been reported by Janssen as inhibitors of RSV in PCT WO 01/36395 (May 25, 2001) and a representative example is shown below. 
Other structurally related compounds are bis-benzimidazoles which possess antifungal activity (B. Cakir, et al. Eczacilik Fak. Derg. 1988, 5, 71). 
Also, H. R. Howard et al. reported a series of benzimidazolone-1-acetic acids that possessed aldolase reductase inhibitory activity (Eur. J. Med. Chem. 1992, 27, 779-789). 
Other prior art related to the chemical structure of the present invention:
(1) F. Sparatore, et al, xe2x80x9cDerivati Benzotriazolici Attivi Sull""accrescimento Delle Piante,xe2x80x9d Il Farmaco Ed. Sci. 1978, 33, 901.
(2) Katritzky, A. R. et al, xe2x80x9cSynthesis and Transformations Of Substituted Benzazolyl- and Tetrazolyl(benzotriazol-1-yl)methanes,xe2x80x9d J. Heterocyclic Chem. 1996, 33, 1107.
(3) Terri A. Fairley, et al. xe2x80x9cStructure, DNA Minor Groove Binding, And Base Pair Specificity of Alkyl and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles), J. Med. Chem. 1993, 36, 1746.
(4) R. K. Upadhyay et al, xe2x80x9cNew Synthesis and Biological Evaluation,xe2x80x9d Indian J. Heterocyclic Chem. 1994, 4, 121.
(5) A. R. Katritzky, et al, xe2x80x9cA New Route to N-substituted Heterocycles,xe2x80x9d Tetrahedron, 1993, 49, 2829.
(6) K. Yu et al. in Substituted Benzimidazole Anti-viral Agents, PCT WO00/04900 published Feb. 3, 2000.
This invention relates to novel heterocyclic substituted 2-methylbenzimidazoles and the antiviral activity against RSV. The structural formula for these compounds are depicted in Formula I, and includes pharmaceutically acceptable salts thereof, 
wherein:
R1 is xe2x80x94(CRaRb)nxe2x80x94X;
Ra, Rb are each independently selected from the group consisting of H, C1-6 alkyl; each of said C1-6 alkyl being optionally substituted with one to six same or different halogen;
X is H or C1-6 alkyl; said C1-6 alkyl being optionally substituted with a member selected from the group consisting of (1) one to six same or different halogen or hydroxy, (2) heteroaryl, (3) non-aromatic heterocyclic ring and (4) a member selected from Group A;
n is 1-6;
Group A is a member selected from the group consisting of halogen, CN, ORx,
N+RcRdRe[Txe2x88x92], NRcRd, CORc, CO2Rx, CONRxRy and S(O)mRc;
Rx and Ry are independently H or C1-6 alkyl;
Rc, Rd and Re are independently C1-6 alkyl;
m is 0-2
Txe2x88x92 is halogen, CF3SO3xe2x88x92 or CH3SO3xe2x88x92;
R2 and R5 are independently halogen or H;
R3 and R4 are each independently selected from the group consisting of H, halogen and C1-6 alkyl; said C1-6 alkyl can be optionally substituted with one to six same or different halogen;
Q is a member selected from the group consisting of 
R6 is selected from the group consisting of H, halogen, NRfRg, SRn and a five-membered heteroaryl containing one to two of the same or different heteroatoms selected from the group consisting of O, S and N;
Rf and Rg are independently H, C1-6 alkyl or C1-6 alkyl; said C1-6 alkyl optionally substituted with ORh or CO2Rh;
Rh and Ri are independently H or C1-6 alkyl;
Rn is C1-6 alkyl optionally substituted with CO2Rh;
R7 is H, or CO2Rh;
R8 is H, CORh, CO2Rh or C1-6 alkyl; said C1-6 alkyl optionally substituted with ORh;
R9 is H, halogen, heteroaryl, phenyl, phenyl substituted with a halogen group, phenyl substituted with a methanesulfonyl group, CORh, CO2Rh, C1-6 alkyl, C2-6 alkenyl, and C2-4 alkynyl; said C2-4 alkynyl optionally substituted with C1-6 cycloalkyl;
R10 and R11 are independently H, NO2 or NRhRi;
R12 is H, CO2Rh or C1-2 alkyl; said C1-2 alkyl optionally substituted with phenyl;
R13 and R14 are independently selected from the group consisting of H, ORh, CONRjRk, NRlRm and pyrrolidine; wherein said pyrrolidine is attached at the nitrogen atom;
Rj and Rk are independently H or C1-6 alkyl optionally substituted with phenyl;
Rl and Rm are independently C1-6 alkyl;
R15 and R16 are independently selected from the group consisting of H, ORh, phenyl, pyridyl and C1-6 alkyl; said C1-6 alkyl optionally substituted with CO2Rh;
R17 and R18 are independently selected from the group consisting of halogen, NRlRm, SRh and morpholine; wherein said morpholine is attached at the nitrogen atom;
R19 is selected from the group consisting of H, phenyl, C2-6 alkenyl and C1-6 alkyl; said C1-6 alkyl optionally substituted with one to six same or different halogen, CO2Rh, CONRhRi, pyridyl and one to three phenyl groups; wherein in the case of C1-6 alkyl substituted with one phenyl group, said phenyl group is optionally substituted with a member selected from the group consisting of halogen, PO(ORh)2, CO2Rh, SO2Rn and CONRhRi;
Rn is C1-6 alkyl;
R20 and R21 are independently H or halogen;
R22 is C1-6 alkyl;
R23 and R24 are independently H or C1-6 alkyl;
R25 is C1-6 cycloalkyl or C1-6 alkyl; said C1-6 alkyl group optionally substituted with a member selected from the group consisting of CO2Rh, PhCO2Rh and one to six same or different halogens;
R26 is selected from the group consisting of H, halogen, C1-6 alkyl; C2-6 alkenyl, ORh and CORh; said C2-6 alkenyl being optionally substituted with ORh;
R27 is H, ORh or CO2Rh;
R28 is CO2Rh;
R29 is H or halogen;
heteroaryl is a 5- or 6-membered aromatic ring containing at least one and up to four non-carbon atoms selected from the group consisting of O, N and S;
non-aromatic heterocyclic ring is a 3 to 7-membered non-aromatic ring containing at least one and up to four non-carbon atoms selected from the group consisting of O, N and S; and
p is 0-2.
In a preferred embodiment, heteroaryl is selected from the group consisting of pyridyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one and tetrazole.
In another preferred embodiment, non-aromatic heterocyclic ring is selected from the group consisting of pyrrolidine and piperidine.
Ra and Rb are hydrogen.
In another preferred embodiment, R1 is xe2x80x94(CH2)nxe2x80x94X and n is 2-4.
In another preferred embodiment, R3 and R4 are each independently selected from the group consisting of H, fluorine and C1-2 alkyl; said C1-2 alkyl being optionally substituted with one to three fluorine atoms.
In another preferred embodiment R1 is 3-methyl-2-butyl or xe2x80x94(CH2)nxe2x80x94X wherein n is 2-4;
X is a member selected from the group consisting of xe2x80x94F, xe2x80x94CN, xe2x80x94SRc, SO2Rc, xe2x80x94ORx, xe2x80x94CORc, CO2Rx, CONRxRy, [NRcRdRe][Txe2x88x92], 
Rc, Rd and Re are independently C1-4 alkyl; and
Rx and Ry are independently H or C1-4 alkyl.
In another preferred embodiment, R2 and R5 are independently H.
Another preferred embodiment includes a pharmaceutical composition which comprises a therapeutically effective amount of one or more of the aforementioned compounds of Formula I, including pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
Another preferred embodiment includes method for treating mammals infected with RSV, and in need thereof, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, including pharmaceutically acceptable salts thereof.
The term pharmaceutically acceptable salt includes solvates, hydrates, acid addition salts and quarternary salts. The acid addition salts are formed from a compound of Formula I and a pharmaceutically acceptable inorganic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, citric, malonic, fumaric, maleic, sulfamic, or tartaric acids. Quaternary salts include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate.
Halogen means bromine, chlorine, iodine and fluorine.